tbuckley/cabot-search huggingface dataset:
Fueling the Tumor Microenvironment with Cancer-Associated Adipocytes
Authors: Caroline Bouche, Daniela F. Quail
Journal: Cancer Research (2023)

Abstract Despite their abundance throughout the body, adipocytes are often ignored for their contributions within the tumor microenvironment (TME). However, their role in fueling cancer is becoming increasingly apparent as interest in the TME has seen remarkable advances in recent years. A seminal study by Dirat and colleagues highlighted the essential impact of the peritumoral adipose tissue in breast cancer progression and was among the first to demonstrate that tumor cells can reprogram adipocytes within their immediate niche to adopt unique characteristics. These “cancer-associated adipocytes” (CAA) were found to exchange cytokines and lipids with tumor cells, leading to their metabolic rewiring and acquisition of proinflammatory and invasive phenotypes. These important discoveries have represented a breakthrough in understanding the bidirectional metabolic dialog between adipocytes and tumor cells, and have contributed renewed perspectives on the functional contributions of adipocytes within the TME. Moreover, the effects of CAA may be further amplified in the setting of obesity as lipids dramatically accumulate, providing insights into the link between breast cancer and its more advanced clinical state in obese conditions. Thus, the different molecular actors involved in the dialog between tumor cells and CAA represent promising therapeutic targets that may have particular relevance in improving prognosis in obese patients with cancer. See related article by Dirat and colleagues, Cancer Res 2011;71:2455–65.
Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101)
Authors: Roberto Carmagnani Pestana, Justin T. Moyers, Jason Roszik, Shiraj Sen, David S. Hong, Aung Naing, Cynthia E. Herzog, Siqing Fu, Sarina A. Piha-Paul, Jordi Rodon, Timothy A. Yap, Daniel D. Karp, Apostolia M. Tsimberidou, Shubham Pant, Maria A. Zarzour, Ravin Ratan, Vinod Ravi, Robert S. Benjamin, Alexander J. Lazar, Wei-Lien Wang, Najat Daw, Jonathan B. Gill, Douglas J. Harrison, Valerae O. Lewis, Christina L. Roland, Shreyaskumar R. Patel, J. Andrew Livingston, Neeta Somaiah, Joseph A. Ludwig, Anthony P. Conley, Nelson Hamerschlak, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma. Experimental Design: In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021. Results: Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P &amp;lt; 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P &amp;lt; 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P &amp;lt; 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P &amp;lt; 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis. Conclusions: Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.
Estimated Costs and Outcomes Associated With Use and Nonuse of Medications for Opioid Use Disorder During Incarceration and at Release in Massachusetts
Authors: Avik Chatterjee, Michelle Weitz, Alexandra Savinkina, Alexandria Macmadu, R. W. M. A. Madushani, Ruth A. Potee, Danielle Ryan, Sean M. Murphy, Alexander Y. Walley, Benjamin P. Linas
Journal: JAMA Network Open (2023)

Importance Most prisons and jails in the US discontinue medications for opioid use disorder (MOUD) upon incarceration and do not initiate MOUD prior to release. Objective To model the association of MOUD access during incarceration and at release with population-level overdose mortality and OUD-related treatment costs in Massachusetts. Design, Setting, and Participants This economic evaluation used simulation modeling and cost-effectiveness with costs and quality-adjusted life-years (QALYs) discounted at 3% to compare MOUD treatment strategies in a corrections cohort and an open cohort representing individuals with OUD in Massachusetts. Data were analyzed between July 1, 2021, and September 30, 2022. Exposures Three strategies were compared: (1) no MOUD provided during incarceration or at release, (2) extended-release (XR) naltrexone offered only at release from incarceration, and (3) all 3 MOUDs (naltrexone, buprenorphine, and methadone) offered at intake. Main Outcomes and Measures Treatment starts and retention, fatal overdoses, life-years and QALYs, costs, and incremental cost-effectiveness ratios (ICERs). Results Among 30 000 simulated incarcerated individuals with OUD, offering no MOUD was associated with 40 927 (95% uncertainty interval [UI], 39 001-42 082) MOUD treatment starts over a 5-year period and 1259 (95% UI, 1130-1323) overdose deaths after 5 years. Over 5 years, offering XR-naltrexone at release led to 10 466 (95% UI, 8515-12 201) additional treatment starts, 40 (95% UI, 16-50) fewer overdose deaths, and 0.08 (95% UI, 0.05-0.11) QALYs gained per person, at an incremental cost of $2723 (95% UI, $141-$5244) per person. In comparison, offering all 3 MOUDs at intake led to 11 923 (95% UI, 10 861-12 911) additional treatment starts, compared with offering no MOUD, 83 (95% UI, 72-91) fewer overdose deaths, and 0.12 (95% UI, 0.10-0.17) QALYs per person gained, at an incremental cost of $852 (95% UI, $14-$1703) per person. Thus, XR-naltrexone only was a dominated strategy (both less effective and more costly) and the ICER of all 3 MOUDs compared with no MOUD was $7252 (95% UI, $140-$10 018) per QALY. Among everyone with OUD in Massachusetts, XR-naltrexone only averted 95 overdose deaths over 5 years (95% UI, 85-169)—a 0.9% decrease in state-level overdose mortality—while the all-MOUD strategy averted 192 overdose deaths (95% UI, 156-200)—a 1.8% decrease. Conclusions and Relevance The findings of this simulation-modeling economic study suggest that offering any MOUD to incarcerated individuals with OUD would prevent overdose deaths and that offering all 3 MOUDs would prevent more deaths and save money compared with an XR-naltrexone–only strategy.
Is Providing Medications for Opioid Use Disorder to Incarcerated Individuals a Cost-effective Strategy?
Authors: Mark Bounthavong
Journal: JAMA Network Open (2023)

Avik Chatterjee, MD, MPH; Michelle Weitz, MS; Alexandra Savinkina, MSPH; Alexandria Macmadu, PhD; R. W. M. A. Madushani, PhD; Ruth A. Potee, MD; Danielle Ryan, MPH; Sean M. Murphy, PhD; Alexander Y. Walley, MD, MSc; Benjamin P. Linas, MD
Amelioration of Fibrotic Remodeling of Human 3‐Dimensional Full‐Thickness Skin by Transglutamase 2 Inhibition
Authors: Xiang Zhou, Thuong Trinh‐Minh, Alexandru‐Emil Matei, Andrea‐Hermina Györfi, Xuezhi Hong, Christina Bergmann, Georg Schett, John Atkinson, Rowann Bowcutt, Jessal Patel, Timothy S. Johnson, Jörg H. W. Distler
Journal: Arthritis & Rheumatology (2023)

Fibrotic tissues are characterized by excessive crosslinking between extracellular matrix (ECM) proteins, rendering them more resistant to degradation. Although increased crosslinking of ECM is thought to play an important role for progression of tissue fibrosis, enhanced ECM crosslinking has not yet been targeted therapeutically in systemic sclerosis (SSc). Here, we investigated the role of transglutaminase 2 (TG2), a central crosslinking enzyme, in the activation of SSc fibroblasts.We assessed TG2 expression and activity using TG2 staining, Western blotting, and TG2 activity assays. We inhibited TG2 in fibroblasts cultured under standard 2-dimensional conditions and in a 3-dimensional full-thickness equivalent skin model using monoclonal inhibitory anti-TG2 antibodies.TG2 expression was increased in the skin of patients with SSc compared with healthy controls, with levels particularly high in patients with SSc-associated interstitial lung disease. TG2 expression and TG2 activity were also increased in SSc dermal fibroblasts. Moreover, the levels of circulating TG2 in the plasma samples from SSc patients were increased versus samples from healthy controls. Anti-TG2 antibodies did not show consistent antifibrotic effects across different fibroblast cell lines under 2-dimensional culture conditions; however, anti-TG2 antibodies effectively reduced transforming growth factor β-induced dermal thickening, myofibroblast differentiation, and collagen accumulation in the 3-dimensional full-thickness model of human skin.We provide the first evidence, to our knowledge, that inhibition of TG2 might be a potential antifibrotic approach in SSc. Our findings have translational potential as anti-TG2 antibodies are currently evaluated in a phase II clinical trial in chronic allograft injury and would thus be available for clinical studies in SSc (ClinicalTrials.gov identifier: NCT04335578).
Comment on ‘Comparison of surgical outcomes and learning curve for robotic versus laparoscopic living donor hepatectomy: a retrospective cohort study’
Authors: Junsheng Gong, Feifan Huang
Journal: International Journal of Surgery (2023)

aDepartment of Hepatobiliary surger, YiWu Central Hospital, Zhejiang 322000, China bDepartment of Clinical Medicine, Wenzhou Medical University, Zhejiang, China Running Title: surgical outcomes and living donor hepatectomy. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Hepatobiliary surger, YiWu Central Hospital, Zhejiang 322000, China. E-mail address: [email protected] (J. Gong). This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.http://creativecommons.org/licenses/by-nc-sa/4.0/
Adherence to Hypertension Guidelines in Children—What Is All the Hype?
Authors: Katja M. Gist, Shina Menon
Journal: JAMA Network Open (2023)

Allison J. Carroll, PhD; Yacob G. Tedla, PhD; Roxane Padilla, MPH; Arjit Jain, MSMIS; Eduardo Segovia, BS; Anoosh Moin, MD; Andrea S. Wallace, PhD, RN; Olutobi A. Sanuade, PhD; Craig B. Langman, MD; Nivedita Mohanty, MD; Justin D. Smith, PhD
Orientated-quantitative computed tomography study on individualized axial safety target area of femoral neck screw channel and establishment of a stable spatial coordinate system based on anterior cortex of femoral neck basilar
Authors: Ying-Sheng Deng, Guang-Liang Jiang, Yu-Fang Cao, Hong-Yi Deng, Hong-Ping Yang, Zhen-Biao Zhu, Duo-Qing Wu, Qiu-Gen Wang
Journal: International Journal of Surgery (2023)

Frequent in-out-in femoral neck screws were reported potential huge iatrogenic-injury risks, related to axial safe target area (ASTA) of femoral neck screws channel. However, orientated-quantitative ASTA based on stable coordinate system was unreported before.Three-dimensional reconstruction was performed on computed tomography (CT) images of 139 intact normal hips, and the intersection area, defined as ASTA, was obtained by superimposing the axial CT images of each femoral neck. Taking anterior cortex of femoral neck basilar (AC-FNB) as landmark, a coordinate system was established to measure the anterior-posterior diameter (D-AP), the superior-inferior diameter (D-SI) and the oblique angle respectively. Each intersection was overlaid up to the axial CT images to determine the coronal location of the ASTA boundaries.Each ASTA presented an inclined rounded triangle with a flat anterior base coincided with AC-FNB. There were significant sex differences in D-SI (male: 33.6±2.3 vs. female: 29.4±1.9 mm) and D-AP (male: 25.3±2.1 vs. 21.9±1.9 mm), P <0.001. D-SI was found to be positively correlated with D-AP ( R2 =0.6). All fluoroscopic visible border isthmus completely matched the corresponding ASTA boundaries. The oblique angle was 5-53° (male: 28.1±10.3°, female: 27.1±8.2°) without significant difference between sexes.The intersection method was employed to conveniently acquire orientated-quantitative individualized ASTA. Under this coordinate system, x-ray data of screws could be converted to axial coordinates in CT ASTA, which could help surgeons design combined screws configuration preoperatively and evaluate quantitatively their axial position intraoperatively.
Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling
Authors: Zuzana Nichtová, Celia Fernandez-Sanz, Sergio De La Fuente, Yuexing Yuan, Stephen Hurst, Sebastian Lanvermann, Hui-Ying Tsai, David Weaver, Ariele Baggett, Christopher Thompson, Cedric Bouchet-Marquis, Péter Várnai, Erin L. Seifert, Gerald W. Dorn, Shey-Shing Sheu, György Csordás
Journal: Circulation Research (2023)

Cardiac contractile function requires high energy from mitochondria, and Ca
Increasing Representation of Black Primary Care Physicians—A Critical Strategy to Advance Racial Health Equity
Authors: Monica E. Peek
Journal: JAMA Network Open (2023)

John E. Snyder, MD, MS, MPH; Rachel D. Upton, PhD; Thomas C. Hassett, PhD; Hyunjung Lee, PhD, MS, MPP, MBA; Zakia Nouri, MA; Michael Dill, MAPP
High-Dimensional Mediation Analysis: A New Method Applied to Maternal Smoking, Placental DNA Methylation, and Birth Outcomes
Authors: Basile Jumentier, Claire-Cécile Barrot, Maxime Estavoyer, Jorg Tost, Barbara Heude, Olivier François, Johanna Lepeule
Journal: Environmental Health Perspectives (2023)

Background: High-dimensional mediation analysis is an extension of unidimensional mediation analysis that includes multiple mediators, and increasingly it is being used to evaluate the indirect omics-layer effects of environmental exposures on health outcomes. Analyses involving high-dimensional mediators raise several statistical issues. Although many methods have recently been developed, no consensus has been reached about the optimal combination of approaches to high-dimensional mediation analyses. Objectives: We developed and validated a method for high-dimensional mediation analysis (HDMAX2) and applied it to evaluate the causal role of placental DNA methylation in the pathway between exposure to maternal smoking (MS) during pregnancy and gestational age (GA) and birth weight of the baby at birth. Methods: HDMAX2 combines latent factor regression models for epigenome-wide association studies with max2 tests for mediation and considers CpGs and aggregated mediator regions (AMRs). HDMAX2 was carefully evaluated using simulated data and compared to state-of-the-art multidimensional epigenetic mediation methods. Then, HDMAX2 was applied to data from 470 women of the Etude des Déterminants pré et postnatals du développement de la santé de l'Enfant (EDEN) cohort. Results: HDMAX2 demonstrated increased power in comparison with state-of-the-art multidimensional mediation methods and identified several AMRs not identified in previous mediation analyses of exposure to MS on birth weight and GA. The results provided evidence for a polygenic architecture of the mediation pathway with a posterior estimate of the overall indirect effect of CpGs and AMRs equal to 44.5g lower birth weight representing 32.1% of the total effect [standard deviation (SD)=60.7g]. HDMAX2 also identified AMRs having simultaneous effects both on GA and on birth weight. Among the top hits of both GA and birth weight analyses, regions located in COASY, BLCAP, and ESRP2 also mediated the relationship between GA and birth weight, suggesting reverse causality in the relationship between GA and the methylome. Discussion: HDMAX2 outperformed existing approaches and revealed an unsuspected complexity of the potential causal relationships between exposure to MS and birth weight at the epigenome-wide level. HDMAX2 is applicable to a wide range of tissues and omic layers. https://doi.org/10.1289/EHP11559
Association of State Supplemental Nutrition Assistance Program Eligibility Policies With Adult Mental Health and Suicidality
Authors: Anna E. Austin, Madeline Frank, Meghan E. Shanahan, H. Luz McNaughton Reyes, Giselle Corbie, Rebecca B. Naumann
Journal: JAMA Network Open (2023)

Importance Food insecurity is associated with an increased likelihood of poor mental health and suicidality. The Supplemental Nutrition Assistance Program (SNAP) is the largest program addressing food insecurity in the US; under broad-based categorical eligibility (BBCE), states have the option to expand SNAP eligibility to a greater number of households by eliminating the asset test or increasing the income limit for eligibility. Objectives To examine the association of state elimination of the asset test and increases in the income limit for SNAP eligibility with rates of mental health and suicidality outcomes among adults. Design, Setting, and Participants This ecological cross-sectional study used 2014 to 2017 data on US adults from the National Vital Statistics System and 2015 to 2019 data on US adults from the National Survey on Drug Use and Health (NSDUH) State-Level Small Area Estimates. Analyses were conducted between September and November 2022. Exposures State elimination of the asset test only and state adoption of both SNAP eligibility policies (ie, state elimination of the asset test and increases in the income limit) for 2014 to 2017 from the SNAP Policy Database. Main Outcomes and Measures Number of adults with a past-year major depressive disorder, mental illness, serious mental illness, or suicidal ideation and number of adults who died by suicide. Results Analyses included 407 391 adult NSDUH participants and 173 085 adults who died by suicide. State elimination of the asset test only was associated with decreased rates of past-year major depressive episodes (rate ratio [RR], 0.92; 95% CI, 0.87-0.98) and mental illness (RR, 0.91; 95% CI, 0.87-0.97) among adults. State adoption of both SNAP eligibility policies (ie, state elimination of the asset test and increases in the income limit) was associated with decreased rates of past-year major depressive episodes (RR, 0.92; 95% CI, 0.86-0.99), mental illness (RR, 0.92; 95% CI, 0.87-0.98), serious mental illness (RR, 0.91; 95% CI, 0.84-0.99), and suicidal ideation (RR, 0.89; 95% CI, 0.82-0.96). Results suggested a decreased rate of suicide death (RR, 0.93; 95% CI, 0.84-1.02) in states with both policies compared with states with neither policy, although this result was not statistically significant. Conclusions and Relevance State adoption of policies that expand SNAP eligibility may contribute to decreased rates of multiple mental health and suicidality outcomes at the population level.
Black Representation in the Primary Care Physician Workforce and Its Association With Population Life Expectancy and Mortality Rates in the US
Authors: John E. Snyder, Rachel D. Upton, Thomas C. Hassett, Hyunjung Lee, Zakia Nouri, Michael Dill
Journal: JAMA Network Open (2023)

Importance Studies have suggested that greater primary care physician (PCP) availability is associated with better population health and that a diverse health workforce can improve care experience measures. However, it is unclear whether greater Black representation within the PCP workforce is associated with improved health outcomes among Black individuals. Objective To assess county-level Black PCP workforce representation and its association with mortality-related outcomes in the US. Design, Setting, and Participants This cohort study evaluated the association of Black PCP workforce representation with survival outcomes at 3 time points (from January 1 to December 31 each in 2009, 2014, and 2019) for US counties. County-level representation was defined as the ratio of the proportion of PCPs who identifed as Black divided by the proportion of the population who identified as Black. Analyses focused on between- and within-county influences of Black PCP representation and treated Black PCP representation as a time-varying covariate. Analysis of between-county influences examined whether, on average, counties with increased Black representation exhibited improved survival outcomes. Analysis of within-county influences assessed whether counties with higher-than-usual Black PCP representation exhibited enhanced survival outcomes during a given year of heightened workforce diversity. Data analyses were performed on June 23, 2022. Main Outcomes and Measures Using mixed-effects growth models, the impact of Black PCP representation on life expectancy and all-cause mortality for Black individuals and on mortality rate disparities between Black and White individuals was assessed. Results A combined sample of 1618 US counties was identified based on whether at least 1 Black PCP operated within a county during 1 or more time points (2009, 2014, and 2019). Black PCPs operated in 1198 counties in 2009, 1260 counties in 2014, and 1308 counties in 2019—less than half of all 3142 Census-defined US counties as of 2014. Between-county influence results indicated that greater Black workforce representation was associated with higher life expectancy and was inversely associated with all-cause Black mortality and mortality rate disparities between Black and White individuals. In adjusted mixed-effects growth models, a 10% increase in Black PCP representation was associated with a higher life expectancy of 30.61 days (95% CI, 19.13-42.44 days). Conclusions and Relevance The findings of this cohort study suggest that greater Black PCP workforce representation is associated with better population health measures for Black individuals, although there was a dearth of US counties with at least 1 Black PCP during each study time point. Investments to build a more representative PCP workforce nationally may be important for improving population health.
TIL Therapy: Facts and Hopes
Authors: Tine J. Monberg, Troels H. Borch, Inge M. Svane, Marco Donia
Journal: Clinical Cancer Research (2023)

Abstract After a positive phase III trial, it is evident that treatment with tumor-infiltrating lymphocytes (TIL) is a safe, feasible, and effective treatment modality for patients with metastatic melanoma. Further, the treatment is safe and feasible in diverse solid tumors, regardless of the histologic type. Still, TIL treatment has not obtained the regulatory approvals to be implemented on a larger scale. Therefore, its availability is currently restricted to a few centers worldwide. In this review, we present the current knowledge of TIL therapy and discuss the practical, logistic, and economic challenges associated with implementing TIL therapy on a larger scale. Finally, we suggest strategies to facilitate the widespread implementation of TIL therapy and approaches to develop the next generation of TILs.